HER2 alterations and prognostic implications in all subtypes of breast cancer.
Authors: Kaitlyn O'Keefe, Andrew Elliott, Chad Livasy, Meghan Steiner, Irene Kang, Dave S. B. Hoon, Wolfgang Michael Korn, Phillip Walker, Milan Radovich, Paula R Pohlmann, Sandra M. Swain, Antoinette R. Tan, Arielle Lutterman Heeke
Journal: Journal of Clinical Oncology (2022)

1041 Background: Amplification or overexpression of human epidermal growth factor receptor 2 (HER2) oncogene is present in about 15-20% of breast cancers &amp; is a prognostic &amp; predictive biomarker. Additional ERBB2/HER2 alterations have become apparent on tumor next generation sequencing (NGS), including activating kinase domain mutations &amp; fusions. Methods: DNA NGS (592 gene panel or whole exome) data from 12,153 breast samples retrospectively reviewed for ERBB2 alterations with RNA whole-transcriptome sequencing (WTS) data available for 7289 (60%) samples. Gene fusions detected using the ArcherDx fusion assay or WTS. Clinicopathologic features were described including breast cancer subtype, age, &amp; biopsy site. HER2 status determined according to 2018 ASCO-CAP guideline. Overall survival obtained from insurance claims &amp; Kaplan-Meier estimates were calculated for defined patient (pt) cohorts. Statistical significance was determined using Chi-square &amp; Wilcoxon rank sum tests. Results: ERBB2 mutations ( ERBB2mts) were identified in 3.2% (n = 388) of tumors overall &amp; most common in liver metastases (113/1972, 5.7%). ERBB2mts were found more in breast lobular tumors compared to ductal tumors (10 vs 2.1%, p &lt; 0.001). HER2+ tumors had higher frequency of ERBB2mts compared to HER2- (4.3 vs 3%, p = 0.028). Tumors with score of 0 by immunohistochemistry demonstrated lower rate of ERBB2mts (0+ 2.2%, 1+ 3.5%, 2+ 4.5%, 3+ 3.45%, p &lt; 0.05). Among HER2- tumors, ERBB2mts were present in 3.6% of hormone receptor (HR)+/HER2- &amp; 1.9% of TNBC. Metastatic tumors had a higher rate of ERBB2mts compared to locoregional breast tumors (3.8 vs 2%, p &lt; 0.001), with increased rates of activating mutations S310F (0.1 vs 0.0%, p &lt; 0.05) &amp; D769H (0.3 vs 0.1%, p &lt; 0.05), &amp; the resistance mutation L755S (1.2 vs 0.6%, p &lt; 0.01). Compared to ERBB2-WT, ERRB2mts were associated with decreased ERBB2 transcripts levels in HER2+ samples (222 vs 441 transcripts per million [TPM], p &lt; 0.001) &amp; increased levels in HER2- samples (73 vs 35 TPM, p &lt; 0.001). High tumor mutational burden (≥ 10 mut/Mb) &amp; ERBB3 mutations were more common in ERBB2mts compared to ERRB2-WT (16.7 vs 7.7%, p &lt; 0.001; 10.6 vs 0.8%, p &lt; 0.001). ERBB2 fusions were rare (0.49%) with 97% occurring in HER2+ tumors. Of 8358 pts with outcome data, prognosis (HR 1.2, P = 0.06) &amp; response to chemotherapy (HR 1.1, P = 0.42) was similar between pts with HER2- ERBB2mt &amp; ERBB2-WT. Conclusions: ERBB2mts &amp; fusions were observed in all breast cancer subtypes - more commonly in HER2+, metastatic, &amp; lobular histology tumors - &amp; did not influence prognosis. These alterations may reflect response to treatment pressures in HER2+ disease to reactivate HER2-mediated growth pathways following anti-HER2 therapy &amp; may represent a targetable upregulated oncogenic pathway in HER2- disease. Ongoing identification of ERBB2 alterations may augment treatment options for breast cancer pts &amp; clinical outcomes from this approach are under investigation.